Imapct of bioMarkers on Pharmacodynamics and Bleeding Risk of Direct Oral AntiCoagulants and Ticagrelor Study II

Official title

Imapct of bioMarkers on Pharmacodynamics and Bleeding Risk of Direct Oral AntiCoagulants and Ticagrelor Study II (IMPACT 2)

Overview

Individual differences in drug efficacy and adverse reactions are common in the clinical application of drugs. Individual differences are caused by many factors, among which genetic factors account for more than 20%. Novel oral anticoagulant drugs (NOACs, including rivaroxaban, apixaban, edoxaban, dabigatran, etc.) and novel antiplatelet drug ticagrelor have the advantages of convenient use and no need for monitoring. But novel oral antithrombotic drugs also increase the risk of bleeding, and there is currently a lack of effective antagonists when antithrombosis is excessive or emergency surgery is required. At present, there are few studies on the causes of individual differences in novel antithrombotic drugs, and there is a lack of predictable biomarkers or drug genotypes, especially in China. Therefore, on the basis of previous studies on NOACs and ticagrelor individualized medication cohorts, this study plans to establish a validation cohort for novel antithrombotic drugs bleeding related biomarkers, conduct multi-omics testing and long-term follow-up, and explore markers related to pharmacodynamics of antithrombotic drugs, adverse bleeding reactions and clinical outcomes.

Interventions

• Genetic Detection of genotype and RNA profile in platelet and white blood cell
  Detection of genotype by next generation sequencing Detection of RNA profile in platelet and white blood cell by RNA sequencing
• Other Indicators test related to coagulation function
  Indicators test including prothrombin time (PT), activated partial thrombin time (APTT), thrombin time (TT), diluted TT (dTT), snake vein enzyme coagulation time (ECT), anti-XA or IIa activity, etc.
• Other Indicators test related to platelet function
  Indicators test related to platelet function. Platelet reactivity was measured by VASP. Platelet aggregation rate was measured by turbidimetric method. Platelet and fibrinolytic function were measured by thrombologram, etc.

Primary outcome measures

• Incidence of new bleeding events [Time frame: Within 1 month after enrollment]
• Incidence of new bleeding events [Time frame: From 1 month to 6 months after enrollment]
• Incidence of new bleeding events [Time frame: From 6 months to 1 year after enrollment]
• Incidence of new bleeding events [Time frame: From 1 year to 2 years after enrollment]
• Incidence of new major cardiovascular events and all-cause death [Time frame: Within 1 month after enrollment]
• Incidence of new major cardiovascular events and all-cause death [Time frame: From 1 month to 6 months after enrollment]
• Incidence of new major cardiovascular events and all-cause death [Time frame: From 6 months to 1 year after enrollment]
• Incidence of new major cardiovascular events and all-cause death [Time frame: From 1 year to 2 years after enrollment]
• Incidence of new thromboembolic events [Time frame: Within 1 month after enrollment]
• Incidence of new thromboembolic events [Time frame: From 1 month to 6 months after enrollment]

Secondary outcome measures (4)

• Genotype detected by next generation sequencing [Time frame: Through study completion, collection only once]
• Expression level of RNA in platelet and white blood cell [Time frame: NOACs: Once each before administration, before and after administration at stable concentration (at least 48h for rivaroxaban, 72h for apixaban or edoxaban). Ticagrelor: Once before administration and once after stable concentration (at least 48h).]
• Anticoagulantion activity evaluation (for NOACs only) [Time frame: Once each before administration, before and after administration at stable concentration (at least 48h for rivaroxaban, 72h for apixaban or edoxaban) .]
• Platelet reactivity evaluation (for Ticagrelor only) [Time frame: Once before administration and once after stable concentration.]

Eligibility criteria

Inclusion criteria

(I) Chinese Patients taking NOACs

• In accordance with anticoagulation indications of NOACs, include prevention of thrombosis in non valvular atrial fibrillation, prevention and treatment of deep vein thrombosis / pulmonary embolism and prevention of thrombosis after knee / hip replacement;
• More than 18 years of age, male or female;
• Never received NOACs in a month and intend to take NOACs or have received NOACs for more than one week continuously;
• sign informed consent.

(II) Chinese Patients taking ticagrelor

• With diagnosis of acute coronary syndrome (ACS), included unstable angina, non ST segment elevation myocardial infarction and ST segment elevation myocardial infarction;
• More than 18 years of age, male or female;
• Never received ticagrelor in a month and intend to take ticagrelor or have received ticagrelor for more than one week continuously#
• sign informed consent.

Exclusion criteria

• With history of immunodeficiency disease, including positive HIV index;
• Positive Hepatitis B surface antigen (HBsAg) and HCV index;
• Combined therapy of CYP3A4 strong inhibitors and P-gp inhibitors (e.g., systemic pyrrole antifungal agents such as ketoconazole, itraconazole, voriconazole and posaconazole; human immunodeficiency virus (HIV) - protease inhibitors such as ritonavir), CYP3A4 strong inducers and P-gp inducers (e.g., rifampicin, phenytoin, phenobarbital, carbamazepine, St. John's Wort, etc.) in 14 days before treatment with NOACs;
• Severe liver dysfunction and abnormal renal function;
• Include contraindications of antithrombosis, such as hypersensitivity, active bleeding, moderate or severe liver disease, previous history of intracranial hemorrhage, gastrointestinal hemorrhage in the past 6 months and major operation within 30 days.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

China · 6 centers

• Anhui Provincial Hospital#The First Affiliated Hospital Of USTC# — Hefei
• Peking University First Hospital — Beijing
• The Second Affiliated Hospital Of Chongqing Medical University — Chongqing
• The 7th People's Hospital of Zhengzhou — Zhengzhou
• Renji Hospital, School of Medicine, Shanghai Jiao Tong University — Shanghai
• Zhongshan Hospital FuDan University — Shanghai

Identifiers

NCT: NCT05764356 · 2022CR67

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗